It has been widely known that nicotine exerts a wide variety of pharmacological effects. These include, for example, cholinergic nervous activation as the effect on central nervous systems such as facilitation of acetylcholine release [De sarno P. & Giacobini E., J. Neurosci. Res., 22, 194-200 (1984)], and further, activation effect on monoaminergic nervous systems [Levin E. D. & Simon B. B., Psychopharmacology, 138, 217-230 (1998)].
It has been also reported that nicotine possesses lots of very useful cerebral function improving effects such as increasing cerebral blood flow and glucose uptake rate in brain [Decker M. W. et al., Life Sci., 56, 545-570 (1995)].
It has been further reported that nicotine inhibits amyloid formation of β-peptides which is believed to be the cause of neuronal cell death during Alzheimer's disease [Salomon A. R. et al., Biochemistry, 35, 13568-13578 (1996)], and have cell protective effects on neuronal cell death induced by β-amyloid (Aβ) [Kihara T. et al., Ann. Neurol., 42, 156-163 (1997)]. Recent studies suggest the possibility of nicotine being a remedy for the inflammatory colitis [Sandborn W. J. et al., Ann. Intern. Med., 126, 364 (1997)].
On the other hand, it is acknowledged that in the patients of Alzheimer's disease, the degeneration of acetylcholinergic neurons known to be one of the important nervous systems responsible for cognition such as attention, learning, memory and recognition, is altered and thus nicotinic acetylcholine receptors in the cerebral cortex and hippocampus are drastically decreased [Nordberg A. et al., J. Neurosci. Res., 31, 103-111 (1992)].
It is reported the possibility of the useful treatment for Alzheimer's disease by activating nicotinic acetylcholine receptors to be recovered the acetylcholine nervous systems mechanism by agonists or modulators of nicotinic acetylcholine receptors [Newhouse P. A. et al., Psychopharmacology, 95, 171-175 (1988)].
The nicotinic acetylcholine receptors belong to the ion channel neurotransmitter receptors composed of five subunits. That is, agonists such as acetylcholine, nicotine and the like are bound to receptors to activate and open the channels thereof, thus causing the influx of cationic ion such as sodium ion from extracellular to result the cell excitation [Galzi J. L. & Changeux J. P., Neuropharmacology, 34, 563-582 (1995)]. The aforementioned agonists such as acetylcholine, nicotine and the like show its effect by binding to the specific site existing in α subunit so-called agonist binding site.
It is known, on the other hand, that compounds such as galantamine and so on which activate cells by potentiating the effects of acetylcholine, have no agonist effect at nicotinic acetylcholine receptors directly. These compounds show their effects through allosteric site which is clearly different from the agonist binding sites [Schrattenholz A. et al., Mol. Pharmacol., 49, 1-6 (1996)].
Mentioned above, compounds capable to activate nicotinic acetylcholine receptors indirectly are called modulators and it is expected to be the practical medicines for treatment of the various neurological diseases [Lin N. -H & Meyer M. D., Exp. Opin. Thr. Patents, 8, 991-1015 (1998)].
The terms “agonists” and “modulators” are used in these definitions in the present specification.
The nicotinic acetylcholine receptors are believed to participate not only in Alzheimer's disease, but also in neurodegenerative diseases such as Parkinson's disease, and many of the neuroses and psychoses such as dementia, anxiety, schizophrenia and so on [Barrantes F. J., in The Nicotic Acetylcholine Receptor, ed. Barrantes F. J., Springer, 1997, p175-212; Lena C. & Changeux J. -P., J. Physiol. (Paris), 92, 63-74 (1998)].
Especially, since it is known that cerebral blood flow of the patients suffering from cerebrovascular dementia caused by cerebral infarction is decreased [Takagi Shigeharu, Gendal Iryo, 28, 1157-1160 (1996); Tachibana H. et al., J. Gerontol., 39, 415-423 (1984)], there seems to be the possibility of agonists of nicotinic acetylcholine receptors or the modulators possessing cerebral blood flow increasing effect to be applied to the medicines in this area of treatment. Furthermore, recent study revealed that agonists of nicotinic acetylcholine receptors and the modulators thereof show analgesic activities [Bannon A. W. et al., Science, 279, 77-81 (1998)].
Nicotine itself surely affects as the agonist of nicotinic acetylcholine receptors. For example, after administration of nicotine to the patients of Alzheimer's disease, the recoveries of their attention or the short-term memory were observed, and also the symptoms of their disease were improved [Newhouse P. A. et al., Drugs & Aging, 11, 206-228 (1997)]. Nevertheless, nicotine also possesses disadvantages such as widely recognized addiction, as well as low bioavailability and severe side effects to the cardiovascular systems.
Therefore, there have been great expectation to develop nicotinic acetylcholine receptors agonists or modulators as medicines in place of nicotine which has no addiction, high bioavailability, and less side effects on cardiovascular systems [Maelicke A. & Albuquerque E. X., Drug Discovery Today, 1, 53-59 (1996); Holladay M. W. et al., J. Med. Chem., 40, 4169-4194 (1997)].
There are some subtypes known as the nicotinic acetylcholine receptors [Shacka J. J. & Robinson S. E. T, Med. Chem. Res., 1996, 444-464], and mainly α4β2 subtype receptors exist in central nervous systems. Furthermore, there exist α1β1γδ (or α1β1εδ) subtype receptors in the neuromuscular junction of motor neurons, and α3β4 subtype receptors in ganglion of autonomic nervous systems and adrenal.
The activation of the cholinergic nervous systems and increasing effect of cerebral blood flow are believed to occur though α4β2 subtype receptors in central nervous systems, and above mentioned effects of nicotine on cardiovascular system are induced by affecting receptor subtypes exist in peripheral nervous system.
Therefore, it may be extremely useful as medicines having no side effects to develop compounds which have no affinity at α1β1γδ subtype nor α3β4 subtype receptors, but selectively affects α4β2 subtype receptors.
In these circumstances, there have been many proposals to develop selective agonists or modulators at nicotinic acetylcholine receptors of central nervous system as practical medicines. These include, for example, the compound such as ABT-418 [Arneric S. P. et al., J. Pharmacol. Exp. Ther., 270, 310-318 (1994); Decker M. W. et al., J. Pharmacol. Exp. Ther., 270, 319-328 (1994)], ABT-089 [Sullivan J. P. et al., J. Pharmacol. Exp. Ther., 283, 235-246 (1997); Decker M. W. et al., J. Pharmacol. Exp. Ther., 283, 247-258 (1997)], GTS-21 [Arendash G. W. et al., Brain Res., 674, 252-259 (1995); Briggs C. A. et al., Pharmacol. Biochem. Behav., 57, 231-241 (1997)], RJR-2403 [Bencherif M. et al., J. Pharmacol. Exp. Ther., 279, 1413-1421 (1996); Lippiello P. M. et al., J. Pharmacol. Exp. Ther., 279, 1422-1429 (1996)], SIB-1508Y [Cosford N. D. P. et al., J. Med. Chem., 39, 3235-3237 (1996); Lloyd. G. K. et al. Life Sci., 1601-1606 (1995)], SIB-1553A [Lloyd. G. K. et al., Life Sci., 62, 1601-1606 (1995)] and so on.
In European Patent Publication EP679397-A2, substituted amine derivatives represented by the following formula were proposed for the medicines for prevention and treatment of cerebral dysfunction.                 in which,        R represents hydrogen, optionally substituted acyl, alkyl, aryl, aralkyl, heteroaryl or heteroarylalkyl radicals;        A represents a monofunctional group of the hydrogen, acyl, alkyl or aryl series or represents a bi-functional group which is linked to the radical Z;        E represents an electron-withdrawing radical;        X represents the —CH═ or ═N— radicals, it being possible for the —CH═ radical to be linked to the Z radical instead of an H atom;        Z represents a monofunctional group of the alkyl, —O—R, —S— R or —NR2 series or represents a bi-functional group which is linked to the A radical or the X radical.        
However, in the compounds disclosed in said patent publication, the E radical is restricted to the electron-withdrawing radical, and therefore, these compounds are clearly different from the compounds disclosed by the present patent application. Furthermore, there is no description in the above-mentioned patent publication that these compounds can selectively activate α4β2 nicotinic acetylcholine receptors.
On the other hand, “imidacloprid”, as a pesticide, is known to have the similar skeleton as the compounds of the present invention. It is confirmed that the imidacloprid electrophysiologically affects as partial agonist at nicotinic acetylcholine receptors of PC12 cell [Nagata K. et al., J. Pharmacol. Exp. Ther., 285, 731-738 (1998)], and imidacloprid itself or its metabolites and their analogues possess affinity to the nicotinic acetylcholine receptors in mouse brain [Lee Chao S. & Casida E., Pestic. Biochem. Physiol., 58, 77-88 (1997); Tomizawa T. & Casida J. E., J. Pharmacol., 127, 115-122 (1999); Latli B. et al., J. Med. Chem., 42, 2227-2234 (1999)], however, there is no report of the imidacloprid derivatives selectively activating α4β2 nicotinic acetylcholine receptors.
Japanese Laid-open Patent Publication Number Hei 10-226684 disclosed [N-(pyridinylmethyl)heterocyclic]ylideneamine compounds represented by the following formula, pharmaceutically acceptable salts and prodrugs thereof.                 in which,        A represents the —CH(R)—;        R3 represents a hydrogen atom or an optionally substituted C1-C6 alkyl; and        B represents the group of the following formula:         
Nevertheless, among the compounds disclosed in said patent publication, the imino group and radical Y in the compounds have no substituent, and therefore, these compounds are clearly different from the compounds of the present invention. It is disclosed that aforementioned compounds possess weak affinity to nicotinic receptors; however, there is no disclosure that these compounds have selective activating effect at α4β2 nicotinic acetylcholine receptors of central nervous systems and act as agonists or modulators of nicotinic acetylcholine receptors.
As mentioned above, there had been many attempts to develop agonists or modulators selectively activating α4β2 nicotinic acetylcholine receptors of central nervous systems via oral administration, but none were satisfactory.